A New Era for Gene Therapy
Emily Whitehead was five years old when physicians diagnosed her with acute lymphoblastic leukemia (ALL), a dangerous form of cancer with a U.S. 5-year survival rate of 68.2% (Cancer Stat Facts). The bubbly little girl was quickly mired in an endless parade of grueling therapies. When these treatments failed to secure a relapse-free recovery, the physicians told her parents to expect the worst, and advised them to put their kindergartener into hospice care.
The Whiteheads were distraught, but they refused to listen to the doctors who had forecasted Emily’s quickly-approaching death. Instead of planning their daughter’s final days and funeral, they went to the Children’s Hospital of Philadelphia for help. There, Emily was enrolled in a clinical trial involving a new technology called CAR-T cell therapy. This gene therapy, the first of its kind, carried significant risks, but Emily didn’t have any other options. Prospects looked gloomy when Emily’s condition plummeted in the two weeks following her treatment with CAR-T cell therapy. But the following week, her treatment team was astonished.
Her biopsy came back with no evidence of cancer.
CAR-T cell therapy has since developed into KymriahTM (tisagenlecleucel), the first gene therapy to be approved by the FDA. Called a “living drug” by pediatric oncologist Dr. Kevin J. Curran, the life-saving treatment was developed through a partnership between the University of Pennsylvania and Novartis. Dr. Carl June, who helped create the treatment, is still stunned. “Now, I have to keep pinching myself to see that this happened,” he said (Grady, 2017).
Kymriah works by harnessing the natural power of the body’s immune soldiers: T-cells. White blood cells, including the aforementioned T-cells, help to regulate and carry out the immune response to any foreign objects or dangerous conditions within the body. In an optimal case, these T-cells would be able to identify cancer cells and destroy them before they are able to do much damage. However, T-cells often cannot recognize cancer cells as something dangerous.
In this form of therapy, T-cells are removed from the patient’s blood and sent to the Novartis lab in Morris Plains, NJ (Grady, 2017). There, researchers use harmless viruses to deliver new genes to the awaiting T-cells. The new genes encode the instructions for how to create Chimeric Antigen Receptors, a surface feature that is then formed on the T-cells. These specialized receptors help the immune cells to identify cancer. Once the T-cells are genetically modified to become CAR T-cells, they are allowed time to multiply and then are shipped back to the medical center serving the patient. The T-cells are funneled back into the patient’s bloodstream, where they can begin the work of defeating the cancer (“Chimeric”). The process takes about 22 days to complete and is given in a single dose.
Unfortunately, the arrival of the genetically-enhanced T-cells can sometimes shock the body into overproduction of cytokines, a type of signaling molecule that regulates the immune system. When this happens, it is called a “cytokine storm,” or Cytokine Release Syndrome (CRS), and this is exactly what caused Emily’s initial and rapid decline before the treatment eventually succeeded. CRS can cause a sudden fever, low blood pressure, and neurological problems, among other issues. While most reactions are mild, some can be fatal. To prevent fatalities, Novartis requires that all facilities using Kymriah must be specially trained and equipped to administer proper CRS treatment. Novartis is certifying only the medical centers that it feels are prepared to safely dispense the drug (Grady, 2017).
Despite the side effects, Kymriah has performed magnificently thus far. In a Phase II drug trial, 83% of the patients–all of whom were severely ill children or young adults–were in remission within three months (“Novartis receives”). Hoping that Kymriah would be able to treat other types of cancer besides ALL, Novartis also ran a trial on adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) that had not succeeded in autologous stem cell transplants. Out of the participants, 30% completely recovered six months into the trial, and 58% experienced some degree of CRS (“Primary Analysis”). In January, the FDA granted Kymriah priority review for this subset of patients. Meanwhile, the European Medicines Agency also granted Kymriah an accelerated assessment process for both young ALL patients and adult DLBCL patients who are ineligible for stem cell treatment (“Novartis granted”). These steps are meant to bring the drug to market more quickly.
Yet the market is precisely what is giving Novartis the most difficult time with Kymriah. Since each treatment must be individually crafted for the patient, each one-time dose will cost $475,000 (Grady, 2017). This is not only a frightening prospect for insurance agencies–who simply may push the brunt of the cost burden on the customer–but also for uninsured patients. Novartis has responded to the outrage by claiming that it carefully reflected upon matters of cost before deciding on the price tag. According to CEO Joseph Jimenez, Novartis “considered many factors including its clinical benefits, the outcomes it provides to patients, and the value it offers to health systems.” In fact, he argues, Kymriah is a bargain, as one assessment “determined a cost-effective price would be $600,000 to $750,000” (Jimenez). After all, the company has already invested and will continue to invest in the time, labor, and research required to develop this drug. All of those investments must inevitably add to the cost. Despite this, Kymriah is still less expensive than the more conventional bone marrow transplant (Grady, 2017). However, Novartis acknowledges that this price will still be impossible for many families to pay. In order to make this treatment accessible to all patients, regardless of socioeconomic status, it has partnered with the Centers for Medicare and Medicaid Services. This partnership aims to bill patients and insurance agencies with “outcome-based pricing:” if an ALL patient does not respond to treatment within the first month, payment is waived completely (“Novartis receives”).
The era of gene therapy has arrived, with all the celebrations and pitfalls that it may harbor. Humans have unlocked the first few puzzles out of thousands involving the genetic code and how it shapes us. Will gene therapy be the panacea it promises to be? Will it lead to a medical revolution of the likes of which have not been seen since penicillin? Are the side effects and ethical arguments worth it, and are there more that we are as yet unaware of? While there is much to be learned, at this point one thing is certain: we have crossed a milestone.
There is no going back.
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Figure 1: A microscopic view of ALL cells
V. (2007, January 15). Acute Leukemia-ALL. Retrieved from https://commons.wikimedia.org/wiki/File:Acute_leukemia-ALL.jpg
Figure 2: DNA holds the instructions for all of life’s processes.
[DNA]. (n.d.). Retrieved from https://pixabay.com/en/dna-biology-medicine-gene-163466/
Figure 3: Genes determine much of our physical and mental health.
[Genetics]. (2016, December 14). Retrieved January 26, 2018, from